ASCO 2025 – vepdegestrant matches rival degraders

Arvinas and Pfizer have long highlighted the difference between their Protac estrogen receptor degrader vepdegestrant and rival oral SERDs, but data being presented at ASCO on Saturday suggest that efficacy is similar across these agents.

One differentiating factor could be side effects, the ASCO presenter told a press conference ahead of the conference. Dr Erika Hamilton of the Sarah Cannon Research Institute highlighted a low incidence of vomiting and diarrhoea with vepdegestrant compared with conventional oral SERDs such as Menarini’s approved Orserdu and Lilly’s investigational imlunestrant.

The big questions now are whether this will be enough to keep Pfizer interested in vepdegestrant, and lure back investors who’ve deserted Arvinas after various setbacks this year.

“Just as much benefit”

Arvinas disclosed in March that the pivotal Veritac-2 trial, in second-line ER-positive HER2-negative breast cancer, had met its primary endpoint of progression-free survival in ESR1 mutants – but failed to show a benefit across an all-comers population.

Now the numbers have been presented for the first time at ASCO. In ESR1m, median PFS was 5.0 months with vepdegestrant, versus 2.1 months with Faslodex, AstraZeneca’s approved injectable SERD.

This looks slightly better than the PFS benefit seen with Lilly’s imlunestrant in its pivotal study, Ember-3, in ESR1m patients. 

Cross-trial comparison of oral oestrogen degraders in second-line ER-positive HER2-negative breast cancer

Note: *study also includes imlunestrant + Verzenio arm. Source: ASCO & OncologyPipeline.

However, when asked how vepdegestrant compared with SERDs, Dr Hamilton hardly gave an overwhelming endorsement of Arvinas’s claims of best-in-class efficacy. “Vepdegestrant is showing just as much PFS benefit as the others, if not a little bit more, when we look numerically.”

Differences between the trials makes a cross-trial comparison even more difficult than usual. Notably, Veritac-2 required patients to have previously received a CDK4/6 inhibitor like Ibrance or Kisqali, while Ember-3 didn’t. This could make the Veritac-2 population tougher to treat – although most patients in Ember-3, around 60%, had in fact received previous CDK4/6 inhibition.

As for overall survival, a key secondary endpoint, Veritac-2 data were immature. In Ember-3 there was a trend towards an OS benefit with imlunestrant monotherapy versus standard of care in ESR1m patients, with a 45% reduction in the risk of death, but the p value of 0.008 didn’t meet the bar for statistical significance.

Protac vs SERD

While traditional SERDs passively degrade the oestrogen receptor, Protacs like vepdegestrant are designed to promote degradation actively. Arvinas previously suggested that this might lead to more potent degradation – something that doesn’t appear to have been shown clinically.

Currently only one oral SERD, Menarini’s Orserdu, has US approval, and only in ESR1m patients. Lilly disclosed in February that it had filed imlunestrant with the FDA, later confirming that it was seeking the go ahead in ESR1m patients only.

AstraZeneca’s camizestrant has also shown a benefit in second-line breast cancer, in the Serena-2 trial back in 2022, but that group doesn’t seem to be taking the project forward in this setting, and instead appears to be focused on first-line disease.

In the front line, Arvinas and Pfizer had been planning a phase 3 trial combining vepdegestrant with Pfizer’s CDK4 inhibitor atirmociclib, but recently abandoned this, along with a second-line vepdegestrant/CDK4/6 inhibitor combo study.

This decision raised questions about Pfizer’s plans for vepdegestrant. The latest data might not have done much to reassure Arvinas investors.